It is estimated that more than 50,000 women in the U.S. will be diagnosed with ductal carcinoma in situ (DCIS, or preinvasive breast cancer) in 2017, and most of the women who receive this diagnosis will be completely asymptomatic.1 In DCIS, the neoplastic cells are confined to the breast ducts;2 thus, in the absence of progression to invasive disease, DCIS has little potential of spreading to distant organs and causing symptoms or death. At present, guidelines recommend that all DCIS be treated with a combination of surgery, radiation, and endocrine therapy—treatments similar to those recommended for patients with invasive cancer. However, it is estimated that without treatment only 20 to 30 percent of DCIS patients will progress to invasive cancer.3,4

The term “overdiagnosis” has been applied in reference to cancerous conditions that are unlikely to cause symptoms or death in a patient’s lifetime.5 An estimated one in four patients is overdiagnosed with breast cancer as a result of mammographic screening, although the absence of standard definitions of overdiagnosis has led to questions about the accuracy of this estimate.6-10 The general consensus, however, is that much of the overdiagnosis burden derives from the treatment of DCIS. For those women who have DCIS that may never have progressed even without treatment, medical intervention can only have harmful effects. And overdiagnosis comes at a financial as well as personal cost—the annual national expenditure incurred by DCIS overtreatment has been estimated to be more than $240 million.11

Advances in epidemiology and cancer biology have clearly established that within the group of diseases categorized as cancer are many conditions that vary enormously in biologic behavior. However, the medical treatment of DCIS has not kept pace with scientific discovery. Surgical and medical oncologists must work to develop a treatment strategy based on biologic risk of clinically significant disease, rather than treating all DCIS as one disease.

For DCIS at low risk of progression to invasive cancer, such as low-grade, small, nonpalpable lesions, surgery and radiation may offer no benefit, whereas large, palpable, high-grade DCIS may require more aggressive approaches to halt the likely progression to invasion. Given the long lead time between the development of DCIS and progression to invasive disease, a case can be made for tailoring intervention by age and the presence of competing comorbidities, as is done for prostate cancer.

COMET study

In a recent Cancer and Leukemia Group B (CALGB) 40903 clinical trial, postmenopausal patients with DCIS were treated with neoadjuvant letrozole to evaluate the magnetic resonance imaging (MRI) and pathologic response to endocrine therapy. Results from this trial are anticipated in the next six months. The COMET (Comparing Operative to Monitoring and Endocrine Therapy for low risk DCIS) Trial builds upon this previous work, to assess outcomes with a less aggressive approach to the management of DCIS, and to continue to advance the knowledge regarding the biologic behavior of DCIS.

COMET is a prospective randomized trial that will assess the risks and benefits associated with active surveillance (AS) versus guideline concordant care (GCC) for patients with low-risk DCIS (see Figure 1). The overarching hypothesis of the study is that management of low-risk DCIS using an AS approach does not yield inferior oncologic or quality of life outcomes when compared with guideline concordant care.

Figure 1. COMET Trial Schema

Patient education and close monitoring will be essential components of the study. Endocrine therapy will be encouraged, but not required, in the active surveillance group, and patients will be followed with mammography every six months to assess for invasive progression. The guideline concordant care group will be treated with surgery, radiation, endocrine therapy, or a combination according to usual care guidelines and followed with mammography every 12 months to assess for recurrent disease. Both groups will be monitored for 10 years. The primary outcome will be the proportion of new diagnoses of ipsilateral invasive cancer in the GCC group and the AS group. Secondary outcomes will include assessment of quality of life between the two arms of the study, as well as long-term survival endpoints.

Inclusion in the COMET Trial will be limited to women ages 40 and older who present with a new diagnosis of DCIS grades I/II. DCIS must be estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive. If human epidermal growth factor receptor 2 (HER2) testing is performed, the DCIS must be HER2 0, 1+, or 2+ by immunohistochemistry (IHC). Male patients, patients with bloody nipple discharge, pregnant patients, or patients with documented history of prior tamoxifen, aromatase inhibitor, or raloxifene use will be excluded. Results from this study will help to determine whether de-escalation of treatment for low-risk DCIS is a feasible approach, and how clinical outcomes and quality of life compare between treatment and surveillance groups.

This trial will recruit 1,200 patients at 100 sites through the Alliance for Clinical Trials in Oncology, with plans to include sites from other national adult cooperative groups. The trial will open for enrollment in February 2017. For more information on the COMET Trial, contact E. Shelley Hwang, MD, MPH, FACS, at shelley.hwang@duke.edu.